The Retroviral Diseases Section of the Medicine Branch conducts clinical and laboratory work aimed at the development of novel therapies for and at the study of HIV infection and related malignancies. One focus of effort is the development of novel therapies for Kaposi' s sarcoma. During the past year, the section has identified paclitaxel as one of the most active drugs against Kaposi's sarcoma (KS), with a 71% major response rate being observed in patients with profound immunodeficiency and extensive KS. In addition, the section has been conducting a Phase I trial of the angiogenesis inhibitor TNP-47O. A PCR assay has been established to identify sequences of a new herpeslike virus, KSHV. Such sequences have been identified in the majority of HIV-infected patients with KS in our clinic, but few HIV-infected patients without KS. A study is underway to retrospectively look at the effect of anti-herpes drugs on this virus in patients with KS. During the past year, we have also determined that non- infectious HIV produced in the presence of the protease inhibitor KNI-272 does not become infectious when the drug is removed. We are presently conducting a Phase I trial of this agent, and preliminary results indicate that it is well absorbed orally. We are also conducting combination studies of AZT and the bis-POM-PMEA (an orally available pro-drug of the acyclic nucleotide PMEA) and of AZT, ddI and nevirapine. A study of betaF- ddA a ddI analogue that does not have cross-reactive resistance with other dideoxynucleosides, is planned in the near future. The section has found that while IL-10 suppresses HIV replication in monocyte/macrophages both IL-12 and IL-4 enhance HIV replication in pre-stimulated T cells. This finding may account for some of the imbalance in Th1-Th2 immunity in HIV infection, particularly the selective loss of Th 1 cells (resulting from their selective stimulating in HIV infection). Dideoxynucleosides block this effect, and we are planning a trial of IL- 12 (a stimulator of Th1 immunity) in combination with dideoxynucleosides in patients with Kaposi's sarcoma.